a) A case report described a patient who developed pericardial effusion after 2 weeks of therapy with mesalamine (500 mg 4 times daily). The patient had symptoms of chest pain and dyspnea on exertion. Chest x-ray revealed cardiac enlargement and a pericardial effusion. The patient's symptoms resolved 2 weeks after discontinuing mesalamine. Previously, the patient had received sulfasalazine with no adverse effects (Jenss et al, 1990). Other case reports of pleuropericarditis manifested by ECG changes, pericardial effusion, and pleural effusion have been described (Gujral et al, 1996).

a) Hypertensive has rarely been reported in patients receiving delayed-release mesalamine during clinical trials (Prod Info LIALDA(R) oral delayed-release tablets, 2011).

a) Tachycardia has rarely been reported in patients receiving delayed-release mesalamine during clinical trials I (Prod Info LIALDA(R) oral delayed-release tablets, 2011).

a) There have been rare reports of pericarditis in published case reports and/or during post marketing surveillance of oral mesalamine and other products that contain or are metabolized to mesalamine (Prod Info Asacol(R) HD oral delayed-release tablet, 2009).
b) ADULT
c) PEDIATRIC

a) Severe bradycardia (28 to 40 bpm) and hypotension (70/50 mmHg) developed in a 29-year-old woman within 24 hours of receiving mesalamine, intravenous steroids, and loperamide for ulcerative colitis. ECG showed sinus bradycardia, sinus pauses, and a junctional escape rhythm. Mesalamine and loperamide were discontinued, and the patient's symptoms resolved within 16 hours. After a second hospitalization for a flare-up of ulcerative colitis, the patient was treated with mesalamine and within 8 hours of dosing developed hypotension and marked bradycardia of 25 to 40 bpm; symptoms again resolved with drug cessation (Asirvatham et al, 1998).

a) Fatal myocarditis has been associated with mesalamine use in one case report (Kristensen et al, 1990).

a) A syndrome of respiratory distress, which includes shortness of breath, chest pain, and pulmonary infiltrates, has been described in several case reports within 48 hours to 6 weeks after the start of therapy (Jain et al, 2010; Lazaro et al, 1997; Sesin et al, 1998; Sentongo & Piccoli, 1998; Guslandi, 1999).
b) CASE REPORT: Respiratory distress, including chest pain, was reported in a 29-year-old woman 48 hours after initiation of therapy with mesalamine (1 gram 3 times/day). Symptoms resolved upon discontinuation. Positive rechallenge was noted 3 weeks later after initiation of mesalamine at 500 mg twice daily for 2 days, which resulted in progressive exertional dyspnea; however, eosinophil count and chest x-ray were normal (Guslandi, 1999).
c) CASE REPORT: A case report described a 30-year-old woman who had been taking oral mesalamine 800 mg twice daily for 8 months for treatment of ulcerative colitis. She presented with a 5-week history of bilateral pleuritic chest pain, increasing shortness of breath, a nonproductive cough, intermittent fevers and a 7 kg weight loss. On examination, there was decreased air entry at both lung bases. The WBC count was 11,300 with 16% eosinophils and a high plasma viscosity. The patient was negative for rheumatoid factor, weakly positive for antinuclear factor, and strongly positive for antibody to neutrophil cytoplasm. A chest x-ray film showed bilateral lung infiltrates and bilateral small pleural effusions. A lung biopsy showed chronic eosinophilic pneumonia. Mesalamine was stopped and the patient's condition improved over the next few weeks. The abnormalities in the chest x-ray film and blood eosinophilia resolved. The authors postulate that pulmonary side effects from mesalamine are rare and may occur soon after the drug is started or after many months of exposure (Honeybourne , 1994).
d) CASE REPORT: Lymphocytic alveolitis and mild interstitial pulmonary fibrosis, induced by mesalamine, were diagnosed in a 70-year-old woman, with successful resolution provided by a dose reduction. Three months after starting mesalamine 2.4 grams/day for ulcerative colitis (UC), the patient reported dry cough and dyspnea on effort. Chest x-ray showed diffuse accentuation of the pulmonary reticulum; small, diffuse opacities were seen on computerized tomography. Pulmonary function testing indicated a restricted pattern. Also, antinuclear antibodies were noted. Rather than withdrawing the drug and initiating corticosteroids, it was decided to continue mesalamine at a reduced dose (1.2 grams/day). After 2 months, pulmonary adverse effects had mitigated, UC had not recurred, and arterial blood gas determinations were within normal limits. After 4 years of follow-up, the patient's UC remained under control with the lowered mesalamine dose. A repeat chest x-ray revealed a reduction of the reticular pattern. Antinuclear and anti-DNA antibody titers were absent. No abnormal pulmonary symptoms had appeared. The authors hypothesized that some case reports of pulmonary hypersensitivity might, in fact, have been dose-dependent toxicities rather than immune-mediated reactions (Sossai et al, 2001).
e) CASE REPORT: Pulmonary toxicity was demonstrated in a 60-year-old patient who was treated with mesalamine for ulcerative colitis. After 4 weeks of treatment, the patient presented with dyspnea, low fever, and had bilateral interstitial infiltrates on x-ray. In addition, blood eosinophils, erythrocyte sedimentation rate, and fibrinogen levels were all abnormal. No organisms could be identified. Once mesalamine was discontinued, the patient's signs and symptoms improved, laboratory parameters returned to normal, and the abnormalities on x-ray resolved within 1 month. Authors suggests that mesalamine was directly responsible for the pulmonary toxicity in this patient (Lazaro et al, 1997a).
f) CASE REPORT: Bilateral pleural effusion with pulmonary infiltrates were observed in a 72-year-old woman following therapy with mesalamine for ulcerative colitis, approximately 6 to 8 weeks after initiation of therapy. In addition, the patient had left ventricular ejection fraction of 45%. The patient's symptoms continued to worsen despite antibiotic and steroid therapy. Symptoms improved within 48 hours of discontinuing mesalamine therapy (Sesin et al, 1998).
g) CASE REPORT: Bronchiolitis obliterans and interstitial pneumonitis occurred in an 18-year-old woman after administration of mesalamine for relapsed ulcerative colitis (UC). The authors suspected that the adverse pulmonary effects were due to mesalamine therapy, but they could not rule out an extraintestinal manifestation of her inflammatory bowel disease. Therapy for the relapse included oral mesalamine, oral 6- mercaptopurine, and mesalamine enemas (during the original UC episode, therapy had included oral mesalamine 1.6 g/day, oral 6- mercaptopurine 50 mg/day, 5-aminosalicylic acid (5-ASA) enemas 4 g/day). After 2 months, the patient reported dyspnea on exertion, nonproductive cough, pleuritic chest pain, and intermittent fever. Antibiotics were ineffective. She was hospitalized with severe dyspnea and hypoxemia. Chest x-rays showed diffuse, patchy, peripheral densities with focal areas of consolidation involving the left lung and thickening of the left pleura. Mesalamine, mercaptopurine, and 5-ASA enemas were discontinued. Left lung biopsy revealed diffusely inflamed and thickened pleura, moderate pleural effusion, pulmonary capillaritis, and intraluminal plugs of granulation tissue in numerous bronchioles (ie, bronchiolitis obliterans). Treatment included intravenous methylprednisolone 40 mg every 6 hours which was tapered to oral prednisone 40 mg once daily. Within 3 weeks, lung infiltrates had almost completely cleared. Mercaptopurine was re-started without recurrence of pulmonary disease (Haralambou et al, 2001).
h) CASE REPORT: A 35-year-old woman with a history of ulcerative colitis developed eosinophilic pneumonia following 6 weeks of therapy with oral mesalamine (1.5 g/day). Symptoms and diagnostic results (chest CT) dramatically improved within 2 weeks of stopping mesalamine; steroid therapy was not required (Tanigawa et al, 1999).
i) CASE REPORT: A 16-year-old boy developed pericarditis complicated by pneumonia with symptoms of shortness of breath, pleuritic chest pain, myalgia, and fever after treatment with mesalamine for 4 weeks. Upon discontinuation of mesalamine, pleural effusions completely resolved within 8 days. A later trial of sulfasalazine (250 mg 3 times daily) resulted in recurrence of symptoms. CT scan revealed atelectasis of the right lung. The patient continued to receive mesalamine and was treated with intravenous antibiotics and a prednisone taper with gradual improvement. Upon rechallenge the patient developed acute symptoms of pleuritic chest pain and shortness of breath 4 to 6 hours after administration, which required hospital admission (Sentongo & Piccoli, 1998).

a) SALICYLATE TOXICITY: Effects of overdose may be similar to salicylate toxicity; hyperventilation and dyspnea may occur (Prod Info LIALDA(R) oral delayed-release tablets, 2011).

a) MESALAMINE: Depression, dizziness, insomnia, somnolence, vertigo, asthenia, and paresthesia have been reported following therapeutic use of mesalamine (Prod Info LIALDA(R) oral delayed-release tablets, 2011; Prod Info APRISO(TM) extended-release oral capsules, 2008; Prod Info Pentasa(R), mesalamine, 1995).

a) SALICYLATE TOXICITY: Effects of overdose may be similar to salicylate toxicity; vertigo, headache, confusion, and drowsiness may occur (Prod Info LIALDA(R) oral delayed-release tablets, 2011).
b) MESALAMINE: CASE REPORT: A 20-year-old man with ulcerative proctitis presented to the emergency department with headache and dizziness 1 to 2 hours after ingesting 7500 mg of mesalamine rectal suppository and taking 7000 mg of the same form rectally. Rectal edema and hyperemia noted on colonoscopy resolved within 15 days and he was discharged to a psychiatric unit (Koseoglu et al, 2011).

a) MESALAMINE: Headache occurred in 11% of patients treated with mesalamine extended-release capsules (n=367) compared with 8% of patients receiving placebo (n=185), according to 2 controlled trials. Mesalamine-treated patients (mean age of 47 years) received extended-release capsules (1.5 grams orally) once daily for 6 months (Prod Info APRISO(TM) extended-release oral capsules, 2008).
b) BALSALAZIDE: Headache has been reported in up to 8% of patients receiving balsalazide disodium (prodrug) therapy (Prod Info COLAZAL(R) oral capsules, 2007).
c) OLSALAZINE: Headache has been reported in up to 5% of patients receiving olsalazine therapy (Prod Info DIPENTUM(R) oral capsules, 2009).

a) SALICYLATE TOXICITY: Effects of overdose may be similar to salicylate toxicity; headache may occur (Prod Info LIALDA(R) oral delayed-release tablets, 2011).

a) SALICYLATE TOXICITY: Effects of overdose may be similar to salicylate toxicity; seizures may occur with severe intoxication (Prod Info LIALDA(R) oral delayed-release tablets, 2011).

a) MESALAMINE: CASE REPORT: A 20-year-old man with ulcerative proctitis intentionally ingested 7500 mg of mesalamine rectal suppository and took 7000 mg of the same form rectally. An initial attempt was made to take the oral and rectal medications rectally; however, he was unsuccessful with this and resorted to taking them orally. He presented to the emergency department with headache, dizziness, nausea, and rectal pain 1 to 2 hours after ingestion. Colonoscopy showed a 1.5 cm ulcer from the anal channel expanding through the rectum and diffuse hyperemia and edema from the anal channel to the proximal rectal mucosa. Rectoscopy 3 months prior showed no pathology. He was treated with gastric lavage, charcoal, IV fluids, sodium bicarbonate, and oral sucralfate. Fifteen days after admission, rectoscopy was normal and he was discharged to a psychiatric unit (Koseoglu et al, 2011).

a) Diarrhea is the most frequently reported gastrointestinal adverse effect of oral mesalamine (Prod Info LIALDA(R) oral delayed-release tablets, 2011; Prod Info APRISO(TM) extended-release oral capsules, 2008; Prod Info Pentasa(R), mesalamine, 1995), and has also occurred with balsalazide or olsalazine (Prod Info DIPENTUM(R) oral capsules, 2009; Prod Info COLAZAL(R) oral capsules, 2007).
b) In pooled data from 3 long-term maintenance studies (one 6-month double-blind comparator and two 12- and 14-month open-label trials), diarrhea was reported in 1.7% (18 of 1082) of patients who received mesalamine delayed-release tablets 1.2 g twice daily or 2.4 g once daily for the maintenance of remission of ulcerative colitis (Prod Info LIALDA(R) oral delayed-release tablets, 2011).
c) CASE REPORT: Severe diarrhea with volume depletion was reported in a 57-year-old man with a history of nongranulomatous enterocolitis one week after rechallenge with mesalamine. Fecal analysis indicated that mesalamine may stimulate leukotriene synthesis resulting in diarrhea or intestinal inflammation as do NSAIDS (Fine et al, 1998).

a) SALICYLATE TOXICITY: Effects of overdose may be similar to salicylate toxicity; diarrhea may occur (Prod Info LIALDA(R) oral delayed-release tablets, 2011).

a) Nausea and vomiting frequently reported following therapeutic use (Prod Info APRISO(TM) extended-release oral capsules, 2008; Prod Info Pentasa(R), mesalamine, 1995), and have also been reported with balsalazide and olsalazine (Prod Info DIPENTUM(R) oral capsules, 2009; Prod Info COLAZAL(R) oral capsules, 2007).

a) SALICYLATE TOXICITY: Effects of overdose may be similar to salicylate toxicity; vomiting may occur (Prod Info LIALDA(R) oral delayed-release tablets, 2011).
b) MESALAMINE: CASE REPORT: A 20-year-old man with ulcerative proctitis presented to the emergency department with nausea 1 to 2 hours after ingesting 7500 mg of mesalamine rectal suppository and taking 7000 mg of the same form rectally. Rectal edema and hyperemia noted on colonoscopy resolved within 15 days and he was discharged to a psychiatric unit (Koseoglu et al, 2011).

a) Abdominal pain and flatulence are frequently reported following therapeutic use (Prod Info LIALDA(R) oral delayed-release tablets, 2011; Prod Info APRISO(TM) extended-release oral capsules, 2008; Prod Info Pentasa(R), mesalamine, 1995), and have also been reported with balsalazide and olsalazine (Prod Info DIPENTUM(R) oral capsules, 2009; Prod Info COLAZAL(R) oral capsules, 2007).

a) MESALAMINE: Mesalamine-induced pancreatitis was reported in a 29-year-old woman with a positive rechallenge. The patient had received mesalamine 2 g daily for 3 days before elevations in serum amylase and lipase were noted. In a review of literature, 29 patients were identified that developed pancreatitis due to sulfasalazine, mesalamine, or olsalazine. In 71.4% of cases, symptoms of acute pancreatitis occurred within the first month of treatment. Positive rechallenge was noted in 17 of 19 cases, even in cases where the dose or derivative drug of 5-aminosalicylic acid were changed (Decocq et al, 1999).
b) MESALAMINE: Acute pancreatitis was described in a 32-year-old woman with Crohn's disease after receiving mesalamine (Asacol(R)) 800 mg 3 times daily for approximately 2 days (in combination with metronidazole). Withdrawal of both mesalamine and metronidazole resulted in normalization of amylase levels within 3 days. Mesalamine was restarted at 400 mg 3 times daily, approximately 6 weeks following the initial episode; acute pancreatitis redeveloped within 48 hours of therapy and resolved after withdrawal of mesalamine. After complete resolution of pancreatitis, a rechallenge with oral mesalamine was initiated (400 mg orally twice daily), resulting in substantial increases in amylase levels following the fourth dose; withdrawal of mesalamine resulted in uneventful recovery. Previous case reports of sulfasalazine-induced pancreatitis were attributed to the sulfapyridine moiety. However, this case report suggests that the aminosalicylate component may be the cause of the acute pancreatitis, despite the low serum levels achieved following oral administration of sulfasalazine (Sachedina et al, 1989). A similar case has been reported (Tran et al, 1991).
c) MESALAMINE: In two 8-week, double-blind, clinical trials, pancreatitis occurred in less than 1% of patients and resulted in discontinuation of mesalamine therapy (Prod Info LIALDA(R) oral delayed-release tablets, 2011).
d) OLSALAZINE: Two children with ulcerative colitis have developed pancreatitis with olsalazine therapy. One of these children had a previous episode of pancreatitis with sulfasalazine therapy and redeveloped pancreatitis after 8 months of olsalazine therapy. Both cases resolved after discontinuation of olsalazine therapy. A third child developed pancreatitis while on sulfasalazine but was able to use olsalazine to treat their condition without the pancreatitis recurring (Garau et al, 1994).

a) Dyspepsia has been reported in clinical trials (Prod Info LIALDA(R) oral delayed-release tablets, 2011; Prod Info Asacol(R) HD oral delayed-release tablet, 2009).

a) Cases of hepatotoxicity, some of which have been fatal, have been reported rarely following mesalamine use. These events have included reports of jaundice, cholestatic jaundice, hepatitis, and possible hepatocellular damage including liver necrosis and liver failure (Prod Info Asacol(R) HD oral delayed-release tablet, 2009).
b) CASE REPORT: A 65-year-old man developed hepatitis after 21 months of mesalamine therapy. Hepatitis resolved after discontinuation of mesalamine, with resolution of abnormal liver enzymes and normalization of antinuclear and anti-smooth muscle antibody titers. In a review of literature, 8 other cases of hepatitis have been reported. Onset of symptoms were reportedly quite variable (6 days to one year) after the initiation of therapy (Deltenre et al, 1999).

a) Mesalamine has been associated with causing renal impairment including minimal change nephropathy, acute and chronic interstitial nephritis, and renal failure (Prod Info APRISO(TM) extended-release oral capsules, 2008; Calvino et al, 1998; Brouillard et al, 1998; Skhiri et al, 1998; Popoola et al, 1998). Interstitial nephritis has also been reported in a patient receiving olsalazine (Wilcox & Reynolds , 1996).

a) SALICYLATE TOXICITY: Effects of overdose may be similar to salicylate toxicity; disruption of blood-pH may occur with severe intoxication (Prod Info LIALDA(R) oral delayed-release tablets, 2011).

a) There have been rare reports of thrombocytopenia in published case reports and/or during postmarketing surveillance of rectal mesalamine and other products that contain or are metabolized to mesalamine (Prod Info Asacol(R) HD oral delayed-release tablet, 2009; Prod Info ROWASA(R) rectal suspension enema, 2005). A patient developed thrombocytopenia and leukopenia after 7 months of treatment with one 500 mg nightly mesalamine suppository (Prod Info CANASA(R) rectal suppositories, 2004).
b) Based upon uncontrolled clinical trials and postmarketing surveillance, a higher incidence of blood dyscrasias has been reported in patients 65 years of age or older who received mesalamine 400 mg delayed-release tablets. Patients with impaired renal function, including elderly patients, may experience a greater risk of toxic reactions with oral mesalamine administration (Prod Info Asacol(R) HD oral delayed-release tablet, 2009; Prod Info ASACOL(R) delayed-release oral tablets, 2007).
c) CASE REPORT: A 25-year-old woman taking mesalamine for ulcerative colitis developed thrombocytopenia which recurred upon rechallenge. Transfusion was required for a platelet count of 9,000 cm(3) (Farrell et al, 1999).
d) CASE REPORT: A 16-year-old girl developed persistent thrombocytopenia (platelets 69,000/cm(3)) after receiving mesalamine for approximately 1 month. After discontinuation of mesalamine and initiation of olsalazine, thrombocytopenia recurred, which also resolved with discontinuation of therapy. An anti-platelet antibody test was negative (Benoit et al, 1999).
e) CASE REPORT: Following the use of mesalamine, thrombocytopenia developed in a patient with polycystic kidney disease, hypertension, Crohn's disease, and progressively deteriorating renal function. The patient had previously received prednisone and sulfasalazine, then mesalamine 800 mg 3 times daily was initiated. The patient's renal function was deteriorating and the patient was admitted for bronchopneumonia and septic shock. Thrombocytopenia appeared to be secondary to myelosuppression and the hypocellular evidence suggested a drug-induced cause. The patient died 5 days later, despite aggressive therapy (Daneshmend, 1991).

a) There have been rare reports of aplastic anemia in published case reports and/or during post marketing surveillance of rectal mesalamine and other products that contain or are metabolized to mesalamine (Prod Info Asacol(R) HD oral delayed-release tablet, 2009; Prod Info ROWASA(R) rectal suspension enema, 2005). Anemia may be part of the clinical presentation of inflammatory bowel disease (Prod Info ROWASA(R) rectal suspension enema, 2005).
b) CASE REPORT: A 71-year-old man with non-insulin-dependent diabetes mellitus was being treated with mesalamine 800 mg twice daily for about 6 months for treatment of ulcerative colitis when he presented with purpura. He was also being treated with prednisolone 5 mg daily. Blood tests showed pancytopenia with a hemoglobin concentration of 88 g/L, white cells 1.3 x 10(9)/L, neutrophils 0.4 x 10(9)/L, and platelets 12 x 10(9)/L. Bone marrow aspirate and trephine biopsy were consistent with severe aplastic anemia. The patient was treated with a 5-day course of rabbit antithymocyte globulin at a dose of 1.5 vials/10 kg of body weight, and regular red cell and platelet transfusions. Four weeks after ATG treatment, the patient died from overwhelming septicemia and pneumonia (Abboudi et al, 1994).
c) CHRONIC TOXICITY

a) There have been rare reports of agranulocytosis in published case reports and/or during post marketing surveillance of rectal mesalamine and other products that contain or are metabolized to mesalamine (Prod Info Asacol(R) HD oral delayed-release tablet, 2009; Prod Info ROWASA(R) rectal suspension enema, 2005).
b) Based upon uncontrolled clinical trials and postmarketing surveillance, a higher incidence of blood dyscrasias such as agranulocytosis, has been reported in patients 65 years of age or older who received mesalamine 400 mg delayed-release tablets. Patients with impaired renal function, including elderly patients, may experience a greater risk of toxic reactions with oral mesalamine administration (Prod Info ASACOL(R) delayed-release oral tablets, 2007).

a) There have been rare reports of neutropenia in published case reports and/or during post marketing surveillance of rectal mesalamine (Prod Info ROWASA(R) rectal suspension enema, 2005).
b) Based upon uncontrolled clinical trials and postmarketing surveillance, a higher incidence of blood dyscrasias, such as neutropenia, has been reported in patients 65 years of age or older who received mesalamine 400-mg delayed-release tablets. Patients with impaired renal function, including elderly patients, may experience a greater risk of toxic reactions with oral mesalamine administration (Prod Info Asacol(R) HD oral delayed-release tablet, 2009; Prod Info ASACOL(R) delayed-release oral tablets, 2007).
c) CASE REPORT: A 73-year-old man developed severe neutropenia following treatment with mesalamine. The patient, whose past medical history was significant for colonic histoplasmosis, was diagnosed with ulcerative colitis and began treatment with mesalamine and itraconazole. Two weeks later, his WBC count was 15,000 cells/mcL and he had an absolute neutrophil count (ANC) of 12,405 cells/mcL. Five months later, the patient was admitted to the ICU with gram-negative sepsis, neutropenic fever, and an ANC of 0. Broad-spectrum antibiotics, including Amphotericin B, were initiated and mesalamine was discontinued due to the rare association with neutropenia. The patient was hemodynamically stable on day one and was transferred out of ICU and continued to clinically improve and remain afebrile. Blood cultures were positive for pseudomonas aeruginosa while fungal cultures and urine histoplasmosis antigen were negative. At the time of discharge on hospital day 4, the patient's ANC had increased to 44 cells/mcL. At four months after hospitalization, his ANC was 2275 cells/mcL and at 8 months after hospitalization his ANC was 3410 cells/mcL and no other complications were reported (Fowler et al, 2010).

a) There have been rare reports of pancytopenia in published case reports and/or during post marketing surveillance of rectal mesalamine (Prod Info ASACOL(R) delayed-release oral tablets, 2007).
b) Based upon uncontrolled clinical trials and postmarketing surveillance, a higher incidence of blood dyscrasias, such as pancytopenia, has been reported in patients 65 years of age or older who received mesalamine 400-mg delayed-release tablets. Patients with impaired renal function, including elderly patients, may experience a greater risk of toxic reactions with oral mesalamine administration (Prod Info Asacol(R) HD oral delayed-release tablet, 2009; Prod Info ASACOL(R) delayed-release oral tablets, 2007).

a) There have been rare reports of eosinophilia in published case reports and/or during post marketing surveillance of rectal mesalamine and other products that contain or are metabolized to mesalamine (Prod Info Asacol(R) HD oral delayed-release tablet, 2009; Prod Info ASACOL(R) delayed-release oral tablets, 2007; Prod Info ROWASA(R) rectal suspension enema, 2005).

a) There have been rare reports of leukopenia in published case reports and/or during post marketing surveillance of oral mesalamine and other products that contain or are metabolized to mesalamine (Prod Info Asacol(R) HD oral delayed-release tablet, 2009; Prod Info ASACOL(R) delayed-release oral tablets, 2007). There have been 2 published reports of a patient who developed thrombocytopenia and leukopenia after 7 months of treatment with one 500 mg nightly suppository (Prod Info CANASA(R) rectal suppositories, 2004)

a) Rash, pruritus, urticaria skin eruption, and alopecia have been reported following mesalamine therapy (Prod Info LIALDA(R) oral delayed-release tablets, 2011; Prod Info APRISO(TM) extended-release oral capsules, 2008; Netzer, 1995; Rao et al, 1987; Kutty et al, 1982).

a) SALICYLATE TOXICITY: Effects of overdose may be similar to salicylate toxicity; sweating may occur (Prod Info LIALDA(R) oral delayed-release tablets, 2011).

a) Two case reports of patients developing lichen planus while receiving oral mesalamine have been presented. Both patients were previously treated with sulfasalazine and lichen planus developed during sulfasalazine treatment. Lesions responded poorly to treatment with griseofulvin and topical steroids; however, they disappeared when mesalamine was withdrawn (Alstead et al, 1991).

a) A case report described severe folliculitis in a 46-year-old man following mesalamine therapy. After starting mesalamine treatment, the patient developed several painless cutaneous lesions (eg, papules and pustules with intense erythema) on his trunk, shoulders, and upper abdomen. The lesions resolved within 4 days of stopping mesalamine treatment. Rechallenge with mesalamine resulted in the appearance of the lesions, but with increased severity. Again, the lesions subsided after stopping mesalamine (Lizasoain et al, 1996).

a) Arthralgia has been reported during therapeutic use of mesalamine and related agents (Prod Info APRISO(TM) extended-release oral capsules, 2008).

a) Hypersensitivity reactions to mesalamine may occur in patients with previous hypersensitivity reaction to sulfasalazine (Prod Info APRISO(TM) extended-release oral capsules, 2008).

a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info GIAZO oral tablets, 2012).

a) Animal studies have revealed no evidence of fetal harm in rats and rabbits administered oral balsalazide up to 2 g/kg/day (2.5 and 4.9 times the recommended human dose, respectively) (Prod Info GIAZO oral tablets, 2012)

a) In animal reproduction studies, no fetal harm was observed at oral doses approximately 0.97 and 1.95 times the recommended human dose based on body surface area (Prod Info ASACOL(R) HD oral delayed-release tablets, 2016)

a) Outcome data were collected on 123 women who had received mesalazine during pregnancy, no increased risk in malformations was reported. The authors concluded that doses of less than 2 grams/day was safe in pregnant women and probably at doses of 3 grams/day (Marteau et al, 1998).

a) It is unknown whether balsalazide or its metabolites are excreted into human milk (Prod Info GIAZO oral tablets, 2012).

a) Low concentrations of mesalamine and higher concentrations of N-acetyl-5-aminosalicylic acid have been detected in breast milk (Prod Info LIALDA(TM) delayed-release oral tablets, 2007; Prod Info Asacol(R), 1994; Prod Info Pentasa(R) mesalamine, 1994; Prod Info APRISO(TM) extended-release oral capsules, 2008; Klotz & Harings-Kaim, 1993). There is no information about the effects of mesalamine on milk production (Prod Info ASACOL(R) HD oral delayed-release tablets, 2016). Unlike maternal oral absorption, any amount of mesalamine appearing in breast milk is likely to be well absorbed by the breastfeeding infant because the infant does not benefit from the delayed-release characteristics of the maternal oral tablets (Nielsen & Bondesen, 1983). Administer mesalamine to a breastfeeding woman only after considering the developmental and health benefits of breastfeeding against the mother's clinical need for mesalamine and the potential risks to the breastfeeding infant (Prod Info ASACOL(R) HD oral delayed-release tablets, 2016; Prod Info LIALDA(TM) delayed-release oral tablets, 2007; Prod Info APRISO(TM) extended-release oral capsules, 2008). Closely monitor infants for changes in stool consistency (Prod Info ASACOL(R) HD oral delayed-release tablets, 2016; Nelis, 1989).

a) Animal studies have revealed no evidence of impaired fertility in rats and rabbits administered oral balsalazide up to 2 g/kg/day (2.5 and 4.9 times the recommended human dose, respectively) (Prod Info GIAZO oral tablets, 2012)

a) In animal studies, mesalamine was found to have no effect on the fertility and reproductive performance of male and female rats (Prod Info ASACOL(R) oral delayed-release tablets, 2015; Prod Info ASACOL(R) HD oral delayed-release tablets, 2016; Prod Info APRISO(TM) extended-release oral capsules, 2008).

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
c) Monitor CBC with differential.

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.

a) ALBUTEROL

a) Consider systemic corticosteroids in patients with significant bronchospasm.
b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).

a) DIPHENHYDRAMINE

a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).

a) EPINEPHRINE

a) OXYGEN: 5 to 10 liters/minute via high flow mask.
b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

a) CARDIAC MONITOR: All complicated cases.
b) IV ACCESS: Routine in all complicated cases.

a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.

a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).

a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.

a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

a) Asacol(R) delayed-release tablet: 800 mg orally 3 times daily for 6 weeks; maximum daily dose of 2.4 g (Prod Info ASACOL(R) oral delayed-release tablets, 2013).
b) Asacol(R) HD delayed-release tablets: 1600 mg (two 800-mg tablets) 3 times daily for 6 weeks (Prod Info ASACOL(R) HD oral delayed-release tablets, 2016).
c) Delzicol(TM) delayed-release capsule: 800 mg (two 400-mg capsules) orally 3 times daily for 6 weeks; maximum daily dose of 2.4 g (Prod Info DELZICOL(R) oral delayed release capsules, 2015).
d) Giazo(R) oral tablet: MEN: 3.3 g orally twice daily for up to 8 weeks; WOMEN: Efficacy not established; not approved for use in women (Prod Info GIAZO oral tablets, 2012).
e) Lialda(TM) delayed-release tablet: 2 to 4 1.2 g tablets taken once daily with meal for a total daily dose of 2.4 or 4.8 g for up to 8 weeks (Prod Info LIALDA(TM) delayed-release oral tablets, 2007).
f) Pentasa(R) controlled-release capsule: 1 gram orally 4 times daily for up to 8 weeks; maximum daily dose 4 g (Prod Info PENTASA(R) controlled-release oral capsules, 2004).
g) Delayed-release tablets and delayed-release capsules should be swallowed whole. They should not be broken, crushed or chewed (Prod Info DELZICOL oral delayed-release capsules, 2014; Prod Info LIALDA(R) oral delayed-release tablets, 2011; Prod Info Asacol(R) HD oral delayed-release tablet, 2009).
h) MAINTENANCE OF REMISSION OF ULCERATIVE COLITIS (ORAL)
i) ACTIVE (RECTAL)
j) ACTIVE, CHRONIC (RECTAL)

a) Canasa(R) suppository: 1000 mg suppository rectally once daily at bedtime (retain for 1 to 3 hours) for 3 to 6 weeks (Prod Info CANASA(R) rectal suppository, 2013).

a) Rowasa(R) enema: 4 g retention enema RECTALLY once daily at bedtime (retain for 8 hours) for 3 to 6 weeks (Prod Info ROWASA(R) rectal suspension enema, 2005).

a) Administer for 6 weeks in children 5 years or older (Prod Info ASACOL(R) oral delayed-release tablets, 2013):

a) Safety and effectiveness have not been established (Prod Info ASACOL(R) HD oral delayed-release tablets, 2016).

a) Administer capsules for a duration of 6 weeks in pediatric patients 5 years of age and older (Prod Info DELZICOL(R) oral delayed release capsules, 2015):
b) WEIGHT 17 TO 32 KG: Recommended dose is 36 to 71 mg/kg/day (maximum 1.2 g/day) orally in 2 divided doses.
c) WEIGHT 33 TO 53 KG: Recommended dose is 37 to 61 mg/kg/day (maximum 2 g/day) orally in 2 divided doses.
d) WEIGHT 54 TO 90 KG: Recommended dose is 27 to 44 mg/kg/day (maximum 2.4 g/day) orally in 2 divided doses.

a) Safety and efficacy have not been established in pediatric patients (Prod Info CANASA(R) rectal suppository, 2013; Prod Info APRISO(TM) extended-release oral capsules, 2008).

a) 5 years and older: Three 750 mg capsules ORALLY 3 times daily (6.75 g/day) for up to 8 weeks, or 750 mg ORALLY 3 times daily (2.25 g/day) for up to 8 weeks (Prod Info COLAZAL(R) oral capsules, 2006).
b) Younger than 5 years: Safety and effectiveness have not been established (Prod Info COLAZAL(R) oral capsules, 2003).

a) Safety and efficacy have not been established in pediatric patients (Prod Info GIAZO oral tablets, 2012).